Fabry disease: genetics, pathology, and treatment

SUMMARY Fabry disease (FD) is a recessive monogenic inheritance disease linked to chromosome X, secondary to mutations in the GLA gene. Its prevalence is estimated between 1:8,454 and 1:117,000 among males and is probably underdiagnosed. Mutations in the GLA gene lead to the progressive accumulation of globotriaosylceramide (Gb3). Gb3 accumulates in lysosomes of different types of cells of the heart, kidneys, skin, eyes, central nervous system, and gastrointestinal system, and may lead to different clinical scenarios. The onset of symptoms occurs during childhood, with acroparesthesia, heat intolerance, and gastrointestinal symptoms, such as nausea, vomiting, abdominal pain, and neuropathic pain. Subsequently, symptoms related to progressive impairment appear, such as angiokeratomas, cornea verticillata, left ventricular hypertrophy, myocardial fibrosis, proteinuria, and renal insufficiency. The latter being the main cause of death in FD. The gold standard for diagnosis is the genetic analysis in search of mutation, in addition to family history. In homozygous patients, the enzyme activity can also be used. Once the diagnosis is confirmed, the patient and their family should receive genetic counseling. The treatment, in turn, currently focuses mainly on replacing the enzyme that is absent or deficient by means of enzyme replacement therapy, with the purpose of avoiding or removing deposits of Gb3. Chaperones can also be used for the treatment of some cases. It is considered that the specific treatment should be initiated as soon as a diagnosis is obtained, which can change the prognosis of the disease.

Familial angiokeratoma corporis diffusum without identified enzyme defect.

Angiokeratoma corporis diffusum is the cutaneous hallmark of several rare inherited lysosomal diseases associated with specific enzyme deficiencies in the metabolism of glycoproteins, most notably Fabry disease. These defects result in many systemic manifestations. Here, we report a rare familial case of angiokeratoma corporis diffusum that developed at puberty with no major systemic manifestations and no underlying enzyme defect or gene mutation. Familial angiokeratoma corporis diffusum without identified enzyme defect appears to be a distinct clinical entity with a benign course.

Fabry disease: clinical and genotypic aspects of three cases in first degree relatives

Fabry disease is an X-linked, lysosomal storage disease caused by the inherited deficiency of the enzyme α-galactosidase A. The diagnosis is usually late, with renal, cardiovascular and/or cerebral complications that reduce life expectancy. Angiokeratomas are asymptomatic lesions present as the initial manifestation and usually less appreciated. Their detection is important for early diagnosis and institution of treatment with enzyme replacement therapy, which prevents late complications reducing morbidity and mortality. We report a case of a male teenager with acroparestesias and angiokeratomas. Family medical research discovered that his mother and brother had similar signs and symptoms and that the three patients had the same mutation in the gene encoding the enzyme, confirming the diagnosis.

Enfermedades por depósito lisosomal: diagnóstico a partir de lesiones cutáneas / Lysosomal storage diseases, diagnosis from skin lesions

Las enfermedades por depósito lisosomal (EDL) son un grupo heterogéneo de más de 40 dolencias genéticas, debidas a la deficiencia de diversas enzimas encargadas de metabolizar sustancias dentrode los lisosomas. Estas macromoléculas se depositan dentro de las organelas de múltiples órganos y dan lugar a diversos signos y síntomas.Muchas de estas enfermedades tienen manifestaciones cutáneas, e incluso en algunas oportunidades es el dermatólogo quien sospecha el diagnóstico a partir de las lesiones en piel.En el presente trabajo se describen 8 pacientes con EDL, diagnosticados en nuestro servicio entre 2009 y 2010, en los cuales las lesiones en piel fueron la clave para arribar al diagnóstico.Cinco pacientes presentaban enfermedad de Fabry (un varón y 4 mujeres), uno mucopolisacaridosis 2 (sexo masculino), uno beta-manosidosis (sexo masculino) y el último galactosialidosis (sexo femenino).Los angioqueratomas fueron la manifestación cutánea más frecuente, y la clave diagnóstica en los pacientes con Fabry, el paciente con manosidosis y la paciente con galactosialidosis, mientras que la lesión en piel que llevó a sospechar mucopolisacaridosis 2 fueron manchas mongólicas aberrantes, algunas lenticulares, que comprometían el tronco.En cuatro pacientes el diagnóstico se confirmó por estudios enzimáticos en gota de sangre en papel de filtro, leucocitos y/u orina. En cinco pacientes (uno de los cuales ya había sido diagnosticado deforma bioquímica) se realizó estudio molecular. En todos los pacientes se hicieron los estudios complementarios necesarios para evaluar extensión del compromiso extracutáneo y necesidad de tratamientoespecífico (en aquellos pacientes en los cuales su enfermedad de base dispone de terapia de reemplazo enzimático). En uno de los pacientes con Fabry se inició terapia específica.El interés de nuestro trabajo radica en mostrar distintas EDL en las cuales el rol del dermatólogo fue fundamental para arribar al diagnóstico, resaltando..

Lysosomal-storage disorders are a group of more than 40 heterogeneous hereditary diseases dueto the deficiency of various lysosomal enzymes, in charge of the metabolization of macromolecules,with accumulation of the undigested substances inside those organelles througout severalorgans, deriving in the multiple symptoms and signs of these diseases.A great number of these diseases may have cutaneous lesions, and in many cases the dermatologistmay be the one to suggest the diagnosis.We describe eight patients with lisosomal storage diseases diagnosed at our hospital during 2009and 2010, on whom the cutaneous lesions were the clue to the diagnosis. Five patients were diagnosed as Fabry´s disease (1 male and 4 females), one as mucopolisaccharidosis2 (male), one as mannosidosis (male) and the last one as galactosyalidosis (female). Angiokeratomaswhere the most frequent cutaneous manifestation, and the key to the diagnosis inFabry’s, beta mannosidosis and galactosyalidosis, while aberrant and lenticular mongolian spotson the trunk led us to the diagnosis of mucopolissacharidosis 2.On four patients the diagnosis was confirmed by biochemical work-up. On five patients (one ofthem had already been confirmed with biochemistry) a genetic study was also performed.On all the patients studies where performed to evaluate the extension of the systemic disease andthe need of a specific treatment (for those diseases where it is available). One of the patients withFabry´s disease started the treatment soon after the diagnosis.We would like to emphasize the fundamental role of the dermatologist in diagnosing these diseases,stressing not only the academic importance of these rare diseases but also the possibility ofstarting in many of them specific enzyme replacement treatment.

Enfermedad de Fabry II: angioqueratoma circunscripto nevoide: presentación de un caso y revisión de la literatura / Fabry's disease II: nevoid circumscribed angiokeratoma: case report and literature review

La angioqueratoma circunscripto nevoide es una malformación de vasos sanguíneos de la dermis, caracterizada por pápulas, nódulos o placas vasculares hiperqueratósicas. Presentamos un paciente de sexo femenino de 18 años de edad que consulta por presentar lesiones verrugosas en miembro inferior derecho de 10 años de evolución. Se realizó biopsia cutánea llegando al diagnóstico de angioqueratoma.

Enfermedad de Fabry-Anderson: angioqueratomas: acroparestesias / Disease of Fabry-Anderson: angioqueratomas: acroparestesias

Paciente de sexo masculino de 32 años de edad que consulta al Servicio de Dermatología por angioqueratomas diseminados y acroparestesias de 20 años de evolución. Con la sospecha de enfermedad de Fabry-Anderson, se solicita dosaje enzimático de alta galactosidasa A, confirmando el diagnóstico.

White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up / Lesões da substância branca na doença de Fabry antes e depois da terapia de reposição enzimática: um seguimento de 2 anos

PURPOSE: To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha. METHOD: Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score). RESULTS: MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared. CONCLUSION: A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.

OBJETIVO: Relatar os achados neurológicos e de imagem do sistema nervoso central (SNC), observados durante 24 meses de tratamento de reposição enzimática (ERT) com agalsidase-alfa, em pacientes com a doença de Fabry (FD). MÉTODO: 8 pacientes foram incluídos; 6 completaram 24 meses de ERT. Os dados foram obtidos aos 0, 12 e 24 meses de ERT. Lesões de substância branca (WML) foram avaliadas assim como sua relação com a idade e o exame neurológico (escore SNC). RESULTADOS: Os achados de ressonância nuclear magnética foram estáveis em 3 pacientes. As WML e o escore SNC pioraram em um caso; flutuaram em um outro caso; e melhoraram no sexto paciente. No todo, havia 15 WML antes da ERT e 19 WML depois de 24 meses de ERT. Em dois anos, 4 lesões desapareceram e 8 novas surgiram. CONCLUSÕES: Viu-se um padrão difuso de WML assintomáticas, na FD. Em dois anos, algumas WML surgiram, enquanto outras desapareceram. Resta demonstrar se esses fenômenos fazem parte da história natural da doença.

Accidente cerebro-vascular en la enfermedad de Fabry: algo más que una simple estenosis / Stroke in Fabry disease: more than a simple stenosis

Se analiza la evidencia existente a la fecha sobre los mecanismos fisiopatológicos que puedem generar accidentes cerebrovasculares en la enfermedad de Fabry. Esta entidad es el resultado de la deficiencia de alfa-galactosidasa A, lo que resulta en depósito patológico de glicoesfingilípidos en distintas poblaciones celulares. Asociados a la insuficiencia renal y cardíaca, los accidentes cerebrovasculares pueden derivar en la muerte de los pacientes. Durante mucho tiempo el único mecanismo generador de daño vascular informado fue la oclusión vascular por depósito lipídico a nivel endotelial. En la actualidad se describen otros mecanismos. El advenimento de la terapia de reemplazo enzimático ha generado gran expectativa en cuanto la posibilidad de reversión de estos mecanismos. Si bien la evidencia es escasa y son necesarios más estudios a largo plazo, algunos informes demuestran que luego de meses, el tratamiento ha logrado revertir algunos de los mecanismos implicados

The objective is to analyze the updated evidence on the physiopathological mechanisms that can generate cerebrovascular damage in Fabry disease. Fabry disease is the result of the deficiency of alpha-galactosidasa A, which causes pathological storage of glycosphingolipids, in different cells. Associated to renal and cardiac insufficiency, cerebrovascular complications can derive in the death of the patients. During a long time the only reported mechanism was the vascular occlusion by deposit of lipids at endothelial level. At the present time, other mechanisms are postulated. The arrival of enzyme replacement therapy has generated great expectation on the possibility of reversion of these alterations. Although the evidence is scarce and more long-term studies are necessary, some reports demonstrate that after months, the treatment has managed to revert some of the mechanisms involved

The ultrastructural study in a case of Fabry disease.

An investigation of the ultrastructural study was conducted on specimens from a typical patient with Fabry disease. Numerous characteristic cytoplasmic inclusions were observed in the vascular endothelial cell, pericyte, smooth muscle cell, nerve and eccrine sweat glands, the lamellar pattern of which were considerably variable in various types of gland cells. Large vacuolar inclusions predominated in clear cells of the secretory coil; lesser vacuoles were also seen in the coiled duct, and the basal cells of the straight duct toward the coiled duct displayed mulberry-like figures. There were some clear cells showing cell damage and necrosis in the secretory coil. Lamellated bodies were noted in the axons and schwann cells around the eccrine sweat glands. The small blood vessels around the eccrine glands were narrowed by swollen endothelial cells with heavy inclusions. These intracytoplasmic deposits may be responsible for the decreased sweating ability in Fabry disease. The factors related to hypohidrosis are also discussed.

Clinicopathologic analysis of 124 biopsy-proven peripheral nerve diseases

We reviewed dinical, histological and ultrastructural findings of 124 cases of sural nerve biopsy specimens to delineate the trends of peripheral nerve diseases in our institute. Eighty-one were men and 43 were women. We categorized them into five groups: specific diagnosis (66 cases, 53.2%), axonal degeneration type (47 cases, 37.9%), demyelinating type (4 cases, 3.2%), mixed axonal degeneration-demyelinating type (6 cases, 4.8%) and normal (1 case, 0.9%). Cases with specific diagnosis included 21 inflammatory demyelinating polyneuropathy (15 chronic inflammatory demyelinating polyradiculoneuropathy, 6 Guillain-Barre disease), 13 hereditary motor and sensory neuropathy (7 Charcot-Marie-Tooth type I, 6 Charcot-Marie-Tooth type II), 10 vasculitis, 6 toxic neuropathy, 4 leprosy, 3 diabetic neuropathy, 2 alcoholic neuropathy, 1 Fabry's disease and other specific diseases (5 cases). In our cases, the proportion of specific diagnoses was higher, while the proportion of demyelinating peripheral neuropathies and normal were lower than those of Western series. The results of this study indicate that 1) a dose clinicopathologic correlation is important to make a precise diagnosis of peripheral nerve biopsy, 2) Biopsy under strict indication may reduce unnecessary histologic examination, 3) There is no difference in disease pattern of peripheral neuropathy between Western people and Koreans.

Fabry's disease: a case report and review of literatures reported in Korea

Fabry's disease is a rare, X-linked disorder of the glycosphingolipid metabolism, in which a partial or total deficiency of a lysosomal alpha(alpha)-galactosidase results in the progressive accumulation of neutral glycosphingolipids with terminal alpha galactose moieties (i.e., cerebroside di- and trihexoside) in most body fluids and tissues. Accumulation of neutral glycosphingolipids occurs within the lysosomes of endothelial, perithelial, and smooth muscle cells of the myocardial and renal systems; to a lesser extent in reticuloendothelial and connective cells of the cornea; and in ganglion and perineural cells of the autonomic nervous system. In Korea, 7 cases of Fabry's disease have been reported. A 29-year-old man with fever and headache had typical skin findings and a family history of Fabry's disease, and it was confirmed through renal biopsy and enzyme assay for alpha-galactosidase. We report a case of Fabry's disease with a review of the literatures reported in Korea.

Angioqueratoma corporis diffusum por deficiencia de Alfa Galactosidasa "A" / Angiokeratoma corporis diffusum due to alpha-galactosidase \"A\" defficiency

Se comunica el caso de un paciente de sexo masculino de 24 años de edad, que presenta angioqueratomas múltiples en todo el tegumento y mucosas, con afectación oftalmológica típica. Se realizó ultramicroscopía de una lesión de piel, donde pudieron verse inclusiones citoplasmáticas en células endoteliales, fibroblastos, células periteliales y perineurales. Bioquímicamente se comprobó la deficiencia enzimática en plasma de la * galactosidasa "A". Se realiza una revisión histórica y se consideran además los aspectos clínicos, histopatológicos, ultramicroscópicos y enzimáticos, como así los distintos diagnósticos diferenciales. También se dan algunas pautas terapéuticas novedosas y otras paliativas. Para finalizar, sugerimos el estudio genético de los familiares directos del paciente para detectar posibles futuros casos y poder brindarles consejo genético adecuado

Angioqueratoma papuloso zoniforme no metamérico (Fabry tipo II) / Zoniform papulous angiokeratoma (Fabry type II)

Se presenta un caso de angioqueratoma papuloso zoniforme no metamérico distribuido por sectores del brazo y antebrazo de una enferma de 43 años de edad, que padecía la enfermedad desde la primera infancia. Esta forma clínica es asimilada con ciertas reservas a la enfermedad de Fabry tipo II, debido a los hechos clínicos tan diferentes que hacen principalmente a la distribución y al aspecto lesional, pequeñas pápulas de uno a cuatro milímetros. Se hace una revisión de todo el conjunto de los angioqueratomas a través de dos de sus clasificaciones más usuales. Se establecen los diagnósticos diferenciales más importantes a los que la variedad neviforme y circunscripta obliga. Se enfatiza la diferenciación de este caso zonal no metamérico y micropapuloso con la forma circunscripta neviforme tradicional de la enfermedad de Fabry tipo II, así como con el Fabry tipo I